Chirality in the new generation of antidepressants: stereoselective analysis of the enantiomers of mirtazapine, N-demethylmirtazapine, and 8-hydroxymirtazapine by LC-MS.

Mirtazapine is an antidepressant that acts specifically on noradrenergic and sertonergic receptors. A LC-MS method was developed that allows the simultaneous analysis of the R-(-)- and S-(+)-enantiomers of mirtazapine (MIR), demethylmirtazapine (DMIR), and 8-hydroxymirtazapine (8-OH-MIR) in plasma of MIR-treated patients. The method involves a 3-step liquid-liquid extraction, an HPLC separation on a Chirobiotic V column, and MS detection in electrospray mode. The limit of quantification (LOQ) for all enantiomers was 0.5 ng/mL, and the intra- and interday CVs were within 3.3% to 11.7% (concentration ranges 5-50 ng/mL). A method is also presented for the quantitative analysis of glucuroconjugated MIR and 8-OH-MIR. S-(+)-8-OH-MIR is present in plasma mainly as its glucuronide. Preliminary data suggest that in all patients, except in those comedicated with CYP2D6 inhibitors such as fluoxetine and thioridazine, R-(-)-MIR concentrations were higher than those of S-(+)MIR. Moreover, fluvoxamine seems also to inhibit the metabolism of MIR. Therefore, this method seems to be suitable for the stereoselective assay of MIR and its metabolites in plasma of patients comedicated with MIR and other drugs for routine and research purposes.

Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study.

We sought to provide a contemporary picture of the presentation, etiology, and outcome of infective endocarditis (IE) in a large patient cohort from multiple locations worldwide. Prospective cohort study of 2781 adults with definite IE who were admitted to 58 hospitals in 25 countries from June 1, 2000, through September 1, 2005. The median age of the cohort was 57.9 (interquartile range, 43.2-71.8) years, and 72.1% had native valve IE. Most patients (77.0%) presented early in the disease (<30 days) with few of the classic clinical hallmarks of IE. Recent health care exposure was found in one-quarter of patients. Staphylococcus aureus was the most common pathogen (31.2%). The mitral (41.1%) and aortic (37.6%) valves were infected most commonly. The following complications were common: stroke (16.9%), embolization other than stroke (22.6%), heart failure (32.3%), and intracardiac abscess (14.4%). Surgical therapy was common (48.2%), and in-hospital mortality remained high (17.7%). Prosthetic valve involvement (odds ratio, 1.47; 95% confidence interval, 1.13-1.90), increasing age (1.30; 1.17-1.46 per 10-year interval), pulmonary edema (1.79; 1.39-2.30), S aureus infection (1.54; 1.14-2.08), coagulase-negative staphylococcal infection (1.50; 1.07-2.10), mitral valve vegetation (1.34; 1.06-1.68), and paravalvular complications (2.25; 1.64-3.09) were associated with an increased risk of in-hospital death, whereas viridans streptococcal infection (0.52; 0.33-0.81) and surgery (0.61; 0.44-0.83) were associated with a decreased risk. In the early 21st century, IE is more often an acute disease, characterized by a high rate of S aureus infection. Mortality remains relatively high.

Substance use and suicidal conduct: a study of adolescents hospitalized for suicide attempt and ideation.

AIM: To study the prevalence of psychoactive substance use disorder (PSUD) among suicidal adolescents, psychoactive substance intoxication at the moment of the attempt, and the association between PSUD at baseline and either occurrence of suicide or repetition of suicide attempt(s). METHODS: 186 adolescents aged 16 to 21 y hospitalized for suicide attempt or overwhelming suicidal ideation were included (T0); 148 of them were traced again for evaluations after 6 mo (T1) and/or 18 mo (T2). DSM-IV diagnoses were assessed each time using the Mini International Neuropsychiatric Interview. RESULTS: At T0, 39.2% of the subjects were found to have a PSUD. Among them, a significantly higher proportion was intoxicated at the time of the attempt than those without PSUD (44.3% vs 25.4%). Among the 148 adolescents who could be traced at either T1 or T2, two died from suicide and 30 repeated suicide attempts once or more times. A marginally significant association was found between death by suicide/repetition of suicide attempt and alcohol abuse/dependence at baseline (OR=3.3, 95% CI 0.7-15.0; OR=2.6, 95% CI 0.7-9.3). More than one suicide attempt before admission to hospital at T0 (OR=3.2, 95% CI 1.1-10.0) and age over 19 y at T0 (OR=3.2, 95% CI 1.1-9.2) were independently associated with the likelihood of death by suicide or repetition of suicide attempt. CONCLUSION: Among adolescents hospitalized for suicide attempt or overwhelming suicidal ideation, the risk of death or repetition of attempt is high and is associated with previous suicide attempts--especially among older adolescents--and also marginally associated with PSUD; these adolescents should be carefully evaluated for such risks and followed up once discharged from the hospital.

Evaluation of exposure biomarkers in offshore workers exposed to low benzene and toluene concentrations.

Characterize ethylbenzene and xylene air concentrations, and explore the biological exposure markers (urinary t,t-muconic acid (t,t-MA) and unmetabolized toluene) among petroleum workers offshore. Offshore workers have increased health risks due to simultaneous exposures to several hydrocarbons present in crude oil. We discuss the pooled benzene exposure results from our previous and current studies and possible co-exposure interactions. BTEX air concentrations were measured during three consecutive 12-h work shifts among 10 tank workers, 15 process operators, and 18 controls. Biological samples were collected pre-shift on the first day of study and post-shift on the third day of the study. The geometric mean exposure over the three work shifts were 0.02 ppm benzene, 0.05 ppm toluene, 0.03 ppm ethylbenzene, and 0.06 ppm xylene. Benzene in air was significantly correlated with unmetabolized benzene in blood (r = 0.69, p < 0.001) and urine (r = 0.64, p < 0.001), but not with urinary t,t-MA (r = 0.27, p = 0.20). Toluene in air was highly correlated with the internal dose of toluene in both blood (r = 0.70, p < 0.001) and urine (r = 0.73, p < 0.001). Co-exposures were present; however, an interaction of metabolism was not likely at these low benzene and toluene exposures. Urinary benzene, but not t,t-MA, was a reliable biomarker for benzene at low exposure levels. Urinary toluene was a useful biomarker for toluene exposure. Xylene and ethylbenzene air levels were low. Dermal exposure assessment needs to be performed in future studies among these workers.

Thyroid function and prevalent and incident metabolic syndrome in older adults: the Health, Ageing and Body Composition Study.

OBJECTIVE: Both subclinical hypothyroidism and the metabolic syndrome have been associated with increased risk of coronary heart disease events. It is unknown whether the prevalence and incidence of metabolic syndrome is higher as TSH levels increase, or in individuals with subclinical hypothyroidism. We sought to determine the association between thyroid function and the prevalence and incidence of the metabolic syndrome in a cohort of older adults. DESIGN: Data were analysed from the Health, Ageing and Body Composition Study, a prospective cohort of 3075 community-dwelling US adults. PARTICIPANTS: Two thousand one hundred and nineteen participants with measured TSH and data on metabolic syndrome components were included in the analysis. MEASUREMENTS: TSH was measured by immunoassay. Metabolic syndrome was defined per revised ATP III criteria. RESULTS: At baseline, 684 participants met criteria for metabolic syndrome. At 6-year follow-up, incident metabolic syndrome developed in 239 individuals. In fully adjusted models, each unit increase in TSH was associated with a 3% increase in the odds of prevalent metabolic syndrome (OR, 1.03; 95% CI, 1.01-1.06; P = 0.02), and the association was stronger for TSH within the normal range (OR, 1.16; 95% CI, 1.03-1.30; P = 0.02). Subclinical hypothyroidism with a TSH > 10 mIU/l was significantly associated with increased odds of prevalent metabolic syndrome (OR, 2.3; 95% CI, 1.0-5.0; P = 0.04); the odds of incident MetS was similar (OR 2.2), but the confidence interval was wide (0.6-7.5). CONCLUSIONS: Higher TSH levels and subclinical hypothyroidism with a TSH > 10 mIU/l are associated with increased odds of prevalent but not incident metabolic syndrome.

Variability of ascending aorta diameter measurements as assessed with electrocardiography-gated multidetector computerized tomography and computer assisted diagnosis software.

Recently, morphometric measurements of the ascending aorta have been done with ECG-gated multidector computerized tomography (MDCT) to help the development of future novel transcatheter therapies (TCT); nevertheless, the variability of such measurements remains unknown. Thirty patients referred for ECG-gated CT thoracic angiography were evaluated. Continuous reformations of the ascending aorta, perpendicular to the centerline, were obtained automatically with a commercially available computer aided diagnosis (CAD). Then measurements of the maximal diameter were done with the CAD and manually by two observers (separately). Measurements were repeated one month later. The Bland-Altman method, Spearman coefficients, and a Wilcoxon signed-rank test were used to evaluate the variability, the correlation, and the differences between observers. The interobserver variability for maximal diameter between the two observers was up to 1.2 mm with limits of agreement [-1.5, +0.9] mm; whereas the intraobserver limits were [-1.2, +1.0] mm for the first observer and [-0.8, +0.8] mm for the second observer. The intraobserver CAD variability was 0.8 mm. The correlation was good between observers and the CAD (0.980-0.986); however, significant differences do exist (P<0.001). The maximum variability observed was 1.2 mm and should be considered in reports of measurements of the ascending aorta. The CAD is as reproducible as an experienced reader.

Generation and characterization of function-blocking anti-ectodysplasin A (EDA) monoclonal antibodies that induce ectodermal dysplasia.

Development of ectodermal appendages, such as hair, teeth, sweat glands, sebaceous glands, and mammary glands, requires the action of the TNF family ligand ectodysplasin A (EDA). Mutations of the X-linked EDA gene cause reduction or absence of many ectodermal appendages and have been identified as a cause of ectodermal dysplasia in humans, mice, dogs, and cattle. We have generated blocking antibodies, raised in Eda-deficient mice, against the conserved, receptor-binding domain of EDA. These antibodies recognize epitopes overlapping the receptor-binding site and prevent EDA from binding and activating EDAR at close to stoichiometric ratios in in vitro binding and activity assays. The antibodies block EDA1 and EDA2 of both mammalian and avian origin and, in vivo, suppress the ability of recombinant Fc-EDA1 to rescue ectodermal dysplasia in Eda-deficient Tabby mice. Moreover, administration of EDA blocking antibodies to pregnant wild type mice induced in developing wild type fetuses a marked and permanent ectodermal dysplasia. These function-blocking anti-EDA antibodies with wide cross-species reactivity will enable study of the developmental and postdevelopmental roles of EDA in a variety of organisms and open the route to therapeutic intervention in conditions in which EDA may be implicated.

Prevalence of overweight and obesity among migrants in Switzerland: association with country of origin.

Migrants tend to present higher overweight and obesity levels, but whether this relationship applies to all nationalities has seldom been studied. The present study aimed to assess the prevalence of overweight and obesity according to nationality in adults. Cross-sectional population-based samples. Five-year nationwide interview surveys (Swiss Health Surveys - SHS) from 1992 to 2007 (n 63 766) and a local examination survey (CoLaus Study in Lausanne 2004-2006, n 6743). Participants were separated into Swiss, French, German, Italian, Portuguese, Spanish nationals, those from the former Republic of Yugoslavia and from other European and other countries. Compared with Swiss nationals, German and French nationals presented a lower prevalence of overweight and obesity, whereas nationals from Italy, Spain, Portugal and the former Republic of Yugoslavia presented higher levels. Adjusting the SHS data for age, gender, education, smoking, leisure-time physical activity and survey year, a lower risk for overweight and obesity was found for German (OR = 0·80, 95 % CI 0·70, 0·92) and French (OR = 0·74, 95 % CI 0·61, 0·89) nationals, whereas higher risks were found for participants from Italy (OR = 1·45, 95 % CI 1·33, 1·58), Spain (OR = 1·36, 95 % CI 1·15, 1·61), Portugal (OR = 1·25, 95 % CI 1·06, 1·47) and the former Republic of Yugoslavia (OR = 1·98, 95 % CI 1·69, 2·32). Similar findings were observed in the CoLaus Study for Italian (OR = 1·63, 95 % CI 1·29, 2·06), Spanish (OR = 1·54, 95 % CI 1·17, 2·04) and Portuguese (OR = 1·49, 95 % CI 1·16, 1·91) participants and for those from the former Republic of Yugoslavia (OR = 5·34, 95 % CI 3·00, 9·50). Overweight and obesity are unevenly distributed among migrants in Switzerland. Migrants from Southern Europe and from the former Republic of Yugoslavia present higher prevalence rates. This suggests that preventive messages should be tailored to these specific populations.

Socio-cultural determinants of adiposity and physical activity in preschool children: a cross-sectional study.

Both individual socio-cultural determinants such as selected parental characteristics (migrant background, low educational level and workload) as well as the regional environment are related to childhood overweight and physical activity (PA). The purpose of the study was to compare the impact of distinct socio-cultural determinants such as the regional environment and selected parental characteristics on adiposity, PA and motor skills in preschool children. Forty preschools (N = 542 children) of two culturally different urban regions (German and French speaking part of Switzerland) participated in the study (Ballabeina Study). Outcome measures included adiposity (BMI and skinfold thickness), objectively measured sedentary activities and PA (accelerometers) and agility performance (obstacle course). Parental characteristics (migrant status, educational level and workload) were assessed by questionnaire. Children from the French speaking areas had higher adiposity, lower levels of total and of more intense PA, were more sedentary and less agile than children from the German speaking regions (percent differences for all outcome parameters except for BMI ≥10%; all p ≤ 0.04). Differences in skinfold thickness, sedentary activities and agility, but not in PA, were also found between children of Swiss and migrant parents, though they were ≤8% (p ≤ 0.02). While paternal workload had no effect, maternal workload and parental education resulted in differences in some PA measures and/or agility performance (percent differences in both: ≤9%, p ≤ 0.008), but not in adiposity or sedentary activities (p = NS). Regional differences in skinfold thickness, PA, sedentary activities and agility performance persisted after adjustment for parental socio-cultural characteristics, parental BMI and, where applicable, children's skinfolds (all p ≤ 0.01). The regional environment, especially the broader social environment, plays a prominent role in determining adiposity, PA and motor skills of young children and should be implicated in the prevention of obesity and promotion of PA in children. clinicaltrials.gov NCT00674544.

Perception of the damaging effects of smoking, and brief cessation counselling by doctors.

An open prospective study was conducted among the patients visiting an urban medical policlinic for the first time without an appointment to assess whether the immigrants (who represent more than half of our patients) are aware of the health effects of smoking, whether the level of acculturation influences knowledge, and whether doctors give similar advice to Swiss and foreign smokers. 226 smokers, 105 Swiss (46.5%), and 121 foreign-born (53.5%), participated in the study. 32.2% (95% CI [24.4%; 41.1%]) of migrants and 9.6% [5.3%; 16.8%] of Swiss patients were not aware of negative effects of smoking. After adjustment for age, the multivariate model showed that the estimated odds of "ignorance of health effects of smoking" was higher for people lacking mastery of the local language compared with those mastering it (odds ratio (OR) = 7.5 [3.6; 15.8], p < 0.001), and higher for men (OR = 4.3 [1.9; 10.0], p < 0.001). Advice to stop smoking was given with similar frequency to immigrants (31.9% [24.2%; 40.8%] and Swiss patients (29.0% [21.0%; 38.5%]). Nonintegrated patients did not appear to receive less counselling than integrated patients (OR = 1.1 [0.6; 2.1], p = 0.812). We conclude that the level of knowledge among male immigrants not integrated or unable to speak the local language is lower than among integrated foreign-born and Swiss patients. Smoking cessation counselling by a doctor was only given to a minority of patients, but such counselling seemed irrespective of nationality.

Weight status and gender-related differences in motor skills and in child care - based physical activity in young children.

Over the last decades, a decline in motor skills and in physical activity and an increase in obesity has been observed in children. However, there is a lack of data in young children. We tested if differences in motor skills and in physical activity according to weight or gender were already present in 2- to 4-year-old children. Fifty-eight child care centers in the French part of Switzerland were randomly selected for the Youp'là bouge study. Motor skills were assessed by an obstacle course including 5 motor skills, derived from the Zurich Neuromotor Assessment test. Physical activity was measured with accelerometers (GT1M, Actigraph, Florida, USA) using age-adapted cut-offs. Weight status was assessed using the International Obesity Task Force criteria (healthy weight vs overweight) for body mass index (BMI). Of the 529 children (49% girls, 3.4 ± 0.6 years, BMI 16.2 ± 1.2 kg/m2), 13% were overweight. There were no significant weight status-related differences in the single skills of the obstacle course, but there was a trend (p = 0.059) for a lower performance of overweight children in the overall motor skills score. No significant weight status-related differences in child care-based physical activity were observed. No gender-related differences were found in the overall motor skills score, but boys performed better than girls in 2 of the 5 motor skills (p ≤ 0.04). Total physical activity as well as time spent in moderate-vigorous and in vigorous activity during child care were 12-25% higher and sedentary activity 5% lower in boys compared to girls (all p < 0.01). At this early age, there were no significant weight status- or gender-related differences in global motor skills. However, in accordance to data in older children, child care-based physical activity was higher in boys compared to girls. These results are important to consider when establishing physical activity recommendations or targeting health promotion interventions in young children.

Increased body fat is independently and negatively related with cardiorespiratory fitness levels in children and adolescents with normal weight.

Body mass index (BMI) is related with cardiorespiratory fitness (CRF), but less is known regarding the combined relationships between BMI and body fat (BF) on CRF. Cross-sectional study included 2361 girls and 2328 boys aged 10–18 years living in the area of Lisbon, Portugal. BMI was calculated by measuring height and weight, and obesity was assessed by international criteria. BF was assessed by bioimpedance. CRF was assessed by the 20-m shuttle run and the participants were classified as normal-to-high or low-CRF level according to Fitness gram criterion-referenced standards. The prevalence of low CRF was 47 and 39% in girls and boys, respectively. The corresponding values for the prevalence of obesity were 4.8 and 5.6% (not significant) and of excess BF of 12.1 and 25.1% (P <0.001), respectively. In both sexes, BMI and BF were inversely related with CRF: r = – 0.53 and – 0.45 for BMI and % BF, respectively, in boys and the corresponding values in girls were – 0.50 and – 0.33 (all P <0.01). When compared with a participant with normal BMI and BF, the odds ratios (95% confidence interval) for low CRF were 1.94 (1.46–2.58) for a participant with normal BMI and high BF, and 6.19 (5.02–7.63) for a participant with high BMI and high BF. The prevalence of low-CRF levels is high in Portuguese youths. BF negatively influences CRF levels among children/adolescents with normal BMI.

Influence of socioeconomic factors on delays, management and outcome amongst patients with acute myocardial infarction undergoing primary percutaneous coronary intervention.

The outcome after primary percutaneous coronary intervention (pPCI) for ST-elevation myocardial infarction (STEMI) is strongly affected by time delays. In this study, we sought to identify the impact of specific socioeconomic factors on time delays, subsequent STEMI management and outcomes in STEMI patients undergoing pPCI, who came from a well-defined region of the French part of Switzerland. A total of 402 consecutive patients undergoing pPCI for STEMI in a large tertiary hospital were retrospectively studied. Symptom-to-first-medical-contact time was analysed for the following socioeconomic factors: level of education, origin and marital status. Main exclusion criteria were: time delay beyond 12 hours, previous treatment with fibrinolytic agents or patients immediately referred for coronary artery bypass graft surgery. Therefore, 222 patients were finally included. At 1 year, there was no difference in mortality between the different socioeconomic groups. Furthermore, there was no difference in management characteristics between them. Symptom-to-first-medical-contact time was significantly longer for patients with a low level of education, Swiss citizens and unmarried patients, with median differences of 23 minutes, 18 minutes and 13 minutes, respectively (p <0.05). Nevertheless, no difference was found regarding in-hospital management and clinical outcome. This study demonstrates that symptom-to-first-medical-contact time is longer amongst people with a lower educational level, Swiss citizens and unmarried people. Because of the low mortality rate in general, these differences in delays did not affect clinical outcomes. Still, tertiary prevention measures should particularly focus on these vulnerable populations.